Pharmacological correction of obesity-induced autophagy arrest using calcium channel blockers

Authors

Hwan-Woo Park, University of Michigan-Ann Arbor
Haeli Park, University of Michigan-Ann Arbor
Ian A. Semple, University of Michigan-Ann Arbor
Insook Jang, University of Michigan-Ann Arbor
Seung-Hyun Ro, University of Michigan-Ann ArborFollow
Myungjin Kim, University of Michigan-Ann Arbor
Victor A. Cazares, University of Michigan-Ann Arbor
Edward L. Stuenkel, University of Michigan-Ann Arbor
Jung-Jae Kim, Nanyang Technological University
Jeong Sig Kim, Nanyang Technological University
Jun Hee Lee, University of Michigan-Ann ArborFollow

Document Type

Article

Date of this Version

2014

Citation

NATURE COMMUNICATIONS | 5:4834

Comments

© 2014 Macmillan Publishers Limited.

DOI: 10.1038/ncomms5834

Abstract

Autophagy deregulation during obesity contributes to the pathogenesis of diverse metabolic disorders. However, without understanding the molecular mechanism of obesity interference in autophagy, development of therapeutic strategies for correcting such defects in obese individuals is challenging. Here we show that a chronic increase of the cytosolic calcium concentration in hepatocytes during obesity and lipotoxicity attenuates autophagic flux by preventing the fusion between autophagosomes and lysosomes. As a pharmacological approach to restore cytosolic calcium homeostasis in vivo, we administered the clinically approved calcium channel blocker verapamil to obese mice. Such treatment successfully increases autophagosome–lysosome fusion in liver, preventing accumulation of protein inclusions and lipid droplets and suppressing inflammation and insulin resistance. As calcium channel blockers have been safely used in clinics for the treatment of hypertension for more than 30 years, our results suggest they may be a safe therapeutic option for restoring autophagic flux and treating metabolic pathologies in obese patients. DOI: 10.1038/ncomms5834 1